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Review
. 2016 Aug 1:103:157-173.
doi: 10.1016/j.addr.2016.01.013. Epub 2016 Jan 29.

Engineering broadly neutralizing antibodies for HIV prevention and therapy

Casey K Hua  1 , Margaret E Ackerman  2
Affiliations
Review

Engineering broadly neutralizing antibodies for HIV prevention and therapy

Casey K Hua et al. Adv Drug Deliv Rev. .

Abstract

A combination of advances spanning from isolation to delivery of potent HIV-specific antibodies has begun to revolutionize understandings of antibody-mediated antiviral activity. As a result, the set of broadly neutralizing and highly protective antibodies has grown in number, diversity, potency, and breadth of viral recognition and neutralization. These antibodies are now being further enhanced by rational engineering of their anti-HIV activities and coupled to cutting edge gene delivery and strategies to optimize their pharmacokinetics and biodistribution. As a result, the prospects for clinical use of HIV-specific antibodies to treat, clear, and prevent HIV infection are gaining momentum. Here we discuss the diverse methods whereby antibodies are being optimized for neutralization potency and breadth, biodistribution, pharmacokinetics, and effector function with the aim of revolutionizing HIV treatment and prevention options.

Keywords: Antibody; Effector function; HIV; Neutralization; Prevention; Therapy.

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Figures

Figure 1
Figure 1
Structure of the HIV Envelope glycoprotein based on the crystal structure of BG505 SOSIP.664 (PDB ID: 4TVP). A] Ribbon representation of HIV gp140 protomer and trimers composed of gp120 (green) and gp41 (purple) subunits. B] Surface structure of HIV Env trimer colored by degree of conservation in the 2014 HIV Sequence Compendium from the LANL database [331]. C] Surface epitope domains colored by contact residues and residues ≤ 4Å from contact residues: V1V2V3 loop/trimer apex (red); V3 glycan-N332 supersite (orange); CD4 binding site (green); gp120-gp41 interface (blue); gp41 membrane-proximal external region (purple). Common bNAbs against each epitope domain are listed. Glycans are not shown, but importantly mask a significant portion of the viral Env surface. Images were generated using the UCSF Chimera package.[332]
Figure 2
Figure 2
Antibodies and antibody-based molecules. A] Cartoon representations of antibody isotypes IgG, monomeric IgA (mIgA), dimeric IgA (dIgA), and secretory IgA (sIgA) are depicted and color coded as follows: heavy chain (blue); light chain (orange); disulfide bonds (black lines); J chain (red); secretory component (purple line). Constant heavy domains 1–3 (CH1-CH3), constant light domain (CL), variable heavy (VH), variable light (VL), antigen-binding fragment (Fab), and crystallizable fragment (Fc) domains are also annotated. B] Antibody-based molecules include the single-chain variable fragment (scFv), antigen-binding fragment (Fab), and scFv-Fc immunoadhesin molecules. Linkers are represented by blue lines. C] CD4-Ig molecules replace scFv/Fab regions with CD4 extracellular domains 1 & 2 (CD4 D1D2 in green). eCD4-Ig additionally includes a C-terminal CCR5 mimetic peptide (CCR5mim1).
Figure 3
Figure 3
Bispecific antibody formats. Cartoon representations of Fab- and scFv-based bispecifics (A), divalent Fc-containing bispecifics (B), and tetravalent bispecific antibody formats (C) are depicted and color-coded by parental mAbs: mAb 1 HC (blue) and LC (orange); mAb 2 HC (purple) and LC (red).
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